Primary progressive aphasia (PPA) is a devastating neurodegenerative syndrome that involves relentless development of aphasia with relative sparing of other cognitive functions, at least early in its course. There are several subtypes that appear to arise as a result of different underlying pathologies. PPA and its subtypes can be difficult to differentiate from other neurodegenerative disorders and from each other, particularly early in their course. Furthermore, there is very little data that would enable the prediction of progression in PPA. Improving our capacity to predict progression would be not only extremely useful for treatment development, but also very valuable for improving our understanding of the basic systems biology of this syndrome. The Principal Investigator of this proposal is a behavioral neurologist who directs the PPA Program at MGH, a multidisciplinary clinical-research program that currently sees approximately one new and two follow-up PPA patients per week. The co-investigator is a systems neuroanatomist who has worked for many years to develop and apply quantitative neuroimaging methods to characterize and measure the topography of large-scale language and other brain networks, and to apply this knowledge to neurologic and psychiatric disorders. We have recently collected preliminary data suggesting that PPA affects specific nodes of cortical language networks, and it progresses in a systematic fashion according to the topography of the network. We propose here to use advanced imaging techniques to refine knowledge of the functional and structural connectivity of the brain's language networks, and to use this knowledge to test the hypothesis that PPA progresses in a predictable fashion within these networks. In addition to adding to our fundamental knowledge of language networks of the brain, this work has the potential to lay a framework for the development of tools for prognostication and monitoring of PPA, which we hope will be useful for the testing of new therapeutic interventions in this devastating neurologic disorder. PUBLIC HEALTH RELEVANCE: Primary progressive aphasia (PPA), a devastating neurodegenerative syndrome that involves relentless development of language impairment. For reasons that are not yet clear, it targets language networks of the brain in a remarkably specific way. This project aims to better define the functional and structural connectivity of large-scale language systems of the brain in order to determine whether this knowledge can be used to predict the progression of the disorder.